Plasma Cell Differentiation, Antibody Quality, and Initial Germinal Center B Cell Population Depend on Glucose Influx Rate.

Serum Ab concentrations, selection for higher affinity BCRs, and generation of higher Ab affinities are important elements of immune response optimization and functions of germinal center (GC) reactions. B cell proliferation requires nutrients to support the anabolism inherent in clonal expansion. Glucose usage by mouse GC B cells has been reported to contribute little to their energy needs, with questions raised as to whether glucose uptake or glycolysis increases in GC B cells compared with their naive precursors. Indeed, metabolism can be highly flexible, such that supply shortage along one pathway may be compensated by increased flux on others. We now show that reduction of the glucose transporter GLUT1 in mice after establishment of a preimmune B cell repertoire, even after initiation of the GC B cell gene expression program, decreased initial GC B cell population numbers, affinity maturation, and plasma cell outputs. Glucose oxidation was heightened in GC B cells, but this hexose flowed more into the pentose phosphate pathway, whose activity was important in controlling reactive oxygen species (ROS) and Ab-secreting cell production. In modeling how glucose usage by B cells promotes the Ab response, the control of ROS appeared insufficient. Surprisingly, the combination of galactose, which mitigated ROS, with provision of mannose, an efficient precursor to glycosylation, supported robust production of and normal Ab secretion by Ab-secreting cells under glucose-free conditions. Collectively, the findings indicate that GCs depend on normal glucose influx, especially in plasma cell production, but reveal an unexpected metabolic flexibility in hexose requirements.

A lifecourse mendelian randomization study highlights the long-term influence of childhood body size on later life heart structure.

Children with obesity typically have larger left ventricular heart dimensions during adulthood. However, whether this is due to a persistent effect of adiposity extending into adulthood is challenging to disentangle due to confounding factors throughout the lifecourse. We conducted a multivariable mendelian randomization (MR) study to separate the independent effects of childhood and adult body size on 4 magnetic resonance imaging (MRI) measures of heart structure and function in the UK Biobank (UKB) study. Strong evidence of a genetically predicted effect of childhood body size on all measures of adulthood heart structure was identified, which remained robust upon accounting for adult body size using a multivariable MR framework (e.g., left ventricular end-diastolic volume (LVEDV), Beta = 0.33, 95% confidence interval (CI) = 0.23 to 0.43, P = 4.6 × 10-10). Sensitivity analyses did not suggest that other lifecourse measures of body composition were responsible for these effects. Conversely, evidence of a genetically predicted effect of childhood body size on various other MRI-based measures, such as fat percentage in the liver (Beta = 0.14, 95% CI = 0.05 to 0.23, P = 0.002) and pancreas (Beta = 0.21, 95% CI = 0.10 to 0.33, P = 3.9 × 10-4), attenuated upon accounting for adult body size. Our findings suggest that childhood body size has a long-term (and potentially immutable) influence on heart structure in later life. In contrast, effects of childhood body size on other measures of adulthood organ size and fat percentage evaluated in this study are likely explained by the long-term consequence of remaining overweight throughout the lifecourse.

Lung function trajectories from school age to adulthood and their relationship with markers of cardiovascular disease risk.

RATIONALE: Lung function in early adulthood is associated with subsequent adverse health outcomes. OBJECTIVES: To ascertain whether stable and reproducible lung function trajectories can be derived in different populations and investigate their association with objective measures of cardiovascular structure and function. METHODS: Using latent profile modelling, we studied three population-based birth cohorts with repeat spirometry data from childhood into early adulthood to identify trajectories of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). We used multinomial logistic regression models to investigate early-life predictors of the derived trajectories. We then ascertained the extent of the association between the derived FEV1/FVC trajectories and blood pressure and echocardiographic markers of increased cardiovascular risk and stroke in ~3200 participants at age 24 years in one of our cohorts. RESULTS: We identified four FEV1/FVC trajectories with strikingly similar latent profiles across cohorts (pooled N=6377): above average (49.5%); average (38.3%); below average (10.6%); and persistently low (1.7%). Male sex, wheeze, asthma diagnosis/medication and allergic sensitisation were associated with trajectories with diminished lung function in all cohorts. We found evidence of an increase in cardiovascular risk markers ascertained by echocardiography (including left ventricular mass indexed to height and carotid intima-media thickness) with decreasing FEV1/FVC (with p values for the mean crude effects per-trajectory ranging from 0.10 to p<0.001). In this analysis, we considered trajectories as a pseudo-continuous variable; we confirmed the assumption of linearity in all the regression models. CONCLUSIONS: Childhood lung function trajectories may serve as predictors in the development of not only future lung disease, but also the cardiovascular disease and multimorbidity in adulthood.

The Ultrasound Window Into Vascular Ageing: A Technology Review by the VascAgeNet COST Action.

Non-invasive ultrasound (US) imaging enables the assessment of the properties of superficial blood vessels. Various modes can be used for vascular characteristics analysis, ranging from radiofrequency (RF) data, Doppler- and standard B/M-mode imaging, to more recent ultra-high frequency and ultrafast techniques. The aim of the present work was to provide an overview of the current state-of-the-art non-invasive US technologies and corresponding vascular ageing characteristics from a technological perspective. Following an introduction about the basic concepts of the US technique, the characteristics considered in this review are clustered into: 1) vessel wall structure; 2) dynamic elastic properties, and 3) reactive vessel properties. The overview shows that ultrasound is a versatile, non-invasive, and safe imaging technique that can be adopted for obtaining information about function, structure, and reactivity in superficial arteries. The most suitable setting for a specific application must be selected according to spatial and temporal resolution requirements. The usefulness of standardization in the validation process and performance metric adoption emerges. Computer-based techniques should always be preferred to manual measures, as long as the algorithms and learning procedures are transparent and well described, and the performance leads to better results. Identification of a minimal clinically important difference is a crucial point for drawing conclusions regarding robustness of the techniques and for the translation into practice of any biomarker.

Puberty timing and markers of cardiovascular structure and function at 25 years: a prospective cohort study.

BACKGROUND: Whether earlier onset of puberty is associated with higher cardiovascular risk in early adulthood is not well understood. Our objective was to examine the association between puberty timing and markers of cardiovascular structure and function at age 25 years. METHODS: We conducted a prospective birth cohort study using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were born between April 1, 1991, and December 31, 1992. Exposure of interest was age at peak height velocity (aPHV), an objective and validated growth-based measure of puberty onset. Outcome measures included cardiovascular structure and function at age 25 years: carotid intima-media thickness (CIMT), left ventricular mass index (LVMI) and relative wall thickness (RWT), pulse wave velocity (PWV) and systolic blood pressure (SBP). Multiple imputation was used to impute missing data on covariates and outcomes. Linear regression was used to examine the association between aPHV and each measure of cardiac structure and function, adjusting for maternal age, gestational age, household social class, maternal education, mother's partner's education, breastfeeding, parity, birthweight, maternal body mass index, maternal marital status, maternal prenatal smoking status and height and fat mass at age 9. All analyses were stratified by sex. RESULTS: A total of 2752-4571 participants were included in the imputed analyses. A 1-year older aPHV was not strongly associated with markers of cardiac structure and function in males and females at 25 years and most results spanned the null value. In adjusted analyses, a 1-year older aPHV was associated with 0.003 mm (95% confidence interval (CI) 0.00001, 0.006) and 0.0008 mm (95% CI - 0.002, 0.003) higher CIMT; 0.02 m/s (95% CI - 0.05, 0.09) and 0.02 m/s (95% CI - 0.04, 0.09) higher PWV; and 0.003 mmHg (95% CI - 0.60, 0.60) and 0.13 mmHg (95% CI - 0.44, 0.70) higher SBP, among males and females, respectively. A 1-year older aPHV was associated with - 0.55 g/m2.7 (95% CI - 0.03, - 1.08) and - 0.89 g/m2.7 (95% CI - 0.45, - 1.34) lower LVMI and - 0.001 (95% CI - 0.006, 0.002) and - 0.002 (95% CI - 0.006, 0.002) lower RWT among males and females. CONCLUSIONS: Earlier puberty is unlikely to have a major impact on pre-clinical cardiovascular risk in early adulthood.

Cardiorespiratory fitness, fatness, and the acute blood pressure response to exercise in adolescence.

OBJECTIVE: Exaggerated exercise blood pressure (BP) is associated with cardiovascular risk factors in adolescence. Cardiorespiratory fitness and adiposity (fatness) are independent contributors to cardiovascular risk, but their interrelated associations with exercise BP are unknown. This study aimed to determine the relationships between fitness, fatness, and the acute BP response to exercise in a large birth cohort of adolescents. METHODS: 2292 adolescents from the Avon Longitudinal Study of Parents and Children (aged 17.8 ± 0.4 years, 38.5% male) completed a sub-maximal exercise step test that allowed fitness (VO2 max ) to be determined from workload and heart rate using a validated equation. Exercise BP was measured immediately on test cessation and fatness calculated as the ratio of total fat mass to total body mass measured by DXA. RESULTS: Post-exercise systolic BP decreased stepwise with tertile of fitness (146 (18); 142 (17); 141 (16) mmHg) but increased with tertile of fatness (138 (15); 142 (16); 149 (18) mmHg). In separate models, fitness and fatness were associated with post-exercise systolic BP adjusted for sex, age, height, smoking, and socioeconomic status (standardized ß: -1.80, 95%CI: -2.64, -0.95 mmHg/SD and 4.31, 95%CI: 3.49, 5.13 mmHg/SD). However, when fitness and fatness were included in the same model, only fatness remained associated with exercise BP (4.65, 95%CI: 3.69, 5.61 mmHg/SD). CONCLUSION: Both fitness and fatness are associated with the acute BP response to exercise in adolescence. The fitness-exercise BP association was not independent of fatness, implying the cardiovascular protective effects of cardiorespiratory fitness may only be realized with more favorable body composition.

Vascular Ageing in Youth: A Call to Action.

Extensive evidence shows that risk factors for cardiovascular disease (CVD) begin to develop early in life. Childhood obesity and elevated blood pressure (BP) have become overwhelmingly challenging, with 57% of today's children predicted to be obese by the age of 35 years, and global rates of hypertension in children and adolescents increasing by 75% from 2000 to 2015. Thus, there is an urgent need for tools that can assess early CVD risk in youth, which may lead to better risk stratification, preventative intervention, and personalised medicine. Vascular ageing (the deterioration in vascular structure and function) is a pivotal progenitor of health degeneration associated with elevated BP. Exposure to adverse environmental and genetic factors from fetal life promotes the development and accumulation of subclinical vascular changes that direct an individual towards a trajectory of early vascular ageing (EVA)-an independent predictor of target organ damage in the heart, brain, and kidneys. Therefore, characterising vascular ageing from youth may provide a window into cardiovascular risk later in life. However, vascular ageing measurements only have value when techniques are accurate/validated and when reliable thresholds are available for defining normal ranges and ranges that signal increased risk of disease. The aim of this paper is to summarise current evidence on the importance of vascular ageing assessment in youth and the impact of interventions to prevent or delay EVA, to highlight the need for standardisation and validation of measurement techniques in children and adolescents, and the importance of establishing reference values for vascular ageing measures in this population.

Sex and Gender Aspects in Vascular Ageing - Focus on Epidemiology, Pathophysiology, and Outcomes.

Sex and gender are important modifiers of cardiovascular system physiology, pathophysiology, and disease development. The atherosclerosis process, together with the progressive loss of arterial elasticity with age, is a major factor influencing the development of overt cardiovascular, renal, and cerebrovascular disease. While differences between women and men in epidemiology and pathophysiology of vascular ageing are increasingly reported, sex-disaggregated data are still scarcely available for prospective studies. A better knowledge of sex differences in physiological ageing as well as in disease-related changes in vascular ageing trajectories is crucial to avoid misdiagnosis and mistreatment. This review presents key concepts and knowledge gaps identified in vascular ageing due to gonadal function, vascular physiology, pathophysiology, psychosocial factors, pregnancy, and prognostic relevance. Gender roles determine the effectiveness of any cardiovascular preventive strategy and acceptance for non-invasive or invasive diagnostics and therapeutics. Gender differences in health behaviour, also due to sociocultural norms conditioned by society, contribute to behaviours that may lead to premature arterial vascular ageing. These include differences in risk behaviours like smoking, diet, exercise, and in stress, but also conditions such as housing, noise pollution, poverty, disability, and any kind of stigmatisation. The VascAgeNet Gender Expert Group aims to advance the use of non-invasive vascular ageing measures in routine clinical settings by providing facts to fill in the gaps concerning sex and gender differences at each step of this process, and to search for solutions.

Youth Vascular Consortium (YVC) Protocol: Establishing Reference Intervals for Vascular Ageing in Children, Adolescents and Young Adults.

BACKGROUND: In the last two decades, the global prevalence of paediatric hypertension increased by approximately 75%. Nearly 25% of children are now classified as obese or overweight. Substantial evidence suggests that risk factors for cardiovascular disease (CVD) begin to develop in childhood, thus warranting the need for tools to better screen for early CVD risk in youth. Vascular ageing, the deterioration of vascular structure and function, may be a potentially useful tool for detecting the early and asymptomatic signs of CVD burden. However, it is currently unclear what differentiates normal from pathological ageing in youth as existing reference values for vascular ageing in youth are limited by small sample size or homogenous populations. The international Youth Vascular Consortium (YVC) has been established to address these issues. AIMS: The primary aim of the YVC is to develop reference intervals of normal vascular ageing in children, adolescents, and young adults. The secondary, exploratory, aim is to perform head-to-head comparisons of vascular ageing biomarkers to determine which biomarker is most strongly related to cardiometabolic health. STUDY DESIGN: The YVC is a retrospective, multicentre study and will collate data on vascular ageing in children (5-12 years), adolescents (13-18 years) and young adults (19-40 years), as well as routine clinical biochemistry, lifestyle, sociodemographic factors and parental health. CONCLUSION: To date, 31 research groups from 19 countries have joined the YVC. To our knowledge, this will be the largest study of its kind to investigate vascular ageing in youth.

The influence of fitness on exercise blood pressure and its association with cardiac structure in adolescence.

PURPOSE: Exaggerated exercise blood pressure (BP) is associated with altered cardiac structure and increased cardiovascular risk. Fitness modifies these associations, but the effect in healthy adolescents is unknown. We performed an observational study to determine the influence of fitness on post-exercise BP, and on its relationship with cardiac structure in adolescents. METHODS: 4835 adolescents from the Avon Longitudinal Study of Parents and Children, (15.4 (0.3) years, 49% male) completed a submaximal cycle test. Fitness was estimated as physical work capacity 170 adjusted for lean body mass and post-exercise BP measured immediately posttest. Cardiovascular structure and function, including left ventricular (LV) mass (n = 1589), left atrium (LA) size (n = 1466), cardiac output (CO, n = 1610), and total peripheral resistance (TPR, n = 1610) were measured at rest by echocardiography 2.4 (0.4) years later. RESULTS: Post-exercise systolic BP increased stepwise by fitness tertile (131.2 mm Hg [130.4, 132.1]; 137.3 mm Hg [136.5, 138.0]; 142.3 mm Hg [141.5, 143.1]). Each 5 mm Hg of post-exercise systolic BP was associated with 2.46 g [1.91, 3.01] greater LV mass, 0.02 cm [0.02, 0.03] greater LA size, and 0.25 g/m2.7 [0.14, 0.36] greater LV mass index. Adjustment for fitness abolished associations (0.29 g [-0.16, 0.74]; 0.01 cm [-0.001, 0.014] and 0.08 g/m2.7 [-0.001, 0.002]). Similar associations between post-exercise systolic BP and each outcome were found between the lowest and highest fitness thirds. CO increased with fitness third (difference 0.06 L/min [-0.05, 0.17]; 0.23 L/min [0.12, 0.34]) while TPR decreased (difference -0.13 mm Hg·min/L [-0.84,0.59]; -1.08 mm Hg·min/L [-0.1.80, 0.35]). CONCLUSIONS: Post-exercise systolic BP increased with fitness, which modified its association with cardiac structure. Higher CO, but lower TPR suggests a physiologically adapted cardiovascular system with greater fitness, highlighting the importance of fitness in adolescence.

Masked hypertension and submaximal exercise blood pressure among adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC).

PURPOSE: Masked hypertension is associated with increased cardiovascular risk but is undetectable by clinic blood pressure (BP). Elevated systolic BP responses to submaximal exercise reveal the presence of masked hypertension in adults, but it is unknown whether this is the case during adolescence. We aimed to determine if exercise BP was raised in adolescents with masked hypertension, and its association with cardiovascular risk markers. METHODS: A total of 657 adolescents (aged 17.7 ± 0.3 years; 41.9% male) from the Avon longitudinal study of parents and children (ALSPAC) completed a step-exercise test with pre-, post-, and recovery-exercise BP, clinic BP and 24-hour ambulatory BP. Masked hypertension was defined as clinic BP <140/90 mm Hg and 24-hour ambulatory BP ≥130/80 mm Hg. Assessment of left-ventricular (LV) mass index and carotid-femoral pulse wave velocity (aortic PWV) was also undertaken. Thresholds of clinic, pre-, post-, and recovery-exercise systolic BP were explored from ROC analysis to identify masked hypertension. RESULTS: Fifty participants (7.8%) were classified with masked hypertension. Clinic, pre-, post-, and recovery-exercise systolic BP were associated with masked hypertension (AUC ≥ 0.69 for all, respectively), with the clinic systolic BP threshold of 115 mm Hg having high sensitivity and specificity and exercise BP thresholds of 126, 150, and 130 mm Hg, respectively, having high specificity and negative predictive value (individually or when combined) for ruling out the presence of masked hypertension. Additionally, this exercise systolic BP above the thresholds was associated with greater left-ventricular mass index and aortic PWV. CONCLUSIONS: Submaximal exercise systolic BP is associated with masked hypertension and adverse cardiovascular structure in adolescents. Exercise BP may be useful in addition to clinic BP for screening of high BP and cardiovascular risk in adolescents.

Differences between brachial and aortic blood pressure in adolescence and their implications for diagnosis of hypertension.

OBJECTIVES: Blood pressure (BP) is the leading global cause of mortality, and its prevalence is increasing in children and adolescents. Aortic BP is lower than brachial BP in adults. We aimed to assess the extent of this difference and its impact on the diagnosis of hypertension among adolescents. METHODS: We used data from 3850 participants from a UK cohort of births in the early 1990s in the Southwest of England, who attended their ∼17-year follow-up and had valid measures of brachial and aortic BP at that clinic [mean (SD) age 17.8 (0.4) years, 66% female individuals]. Data are presented as mean differences [95% prediction intervals] for both sexes. RESULTS: Aortic systolic BP (SBP) was lower than brachial SBP [male, -22.3 (-31.2, -13.3) mmHg; female, -17.8 (-25.5, -10.0) mmHg]. Differences between aortic and brachial diastolic BP (DBP) were minimal. Based on brachial BP measurements, 101 male individuals (6%) and 22 female individuals (1%) were classified as hypertensive. In contrast, only nine male individuals (<1%) and 14 female individuals (<1%) met the criteria for hypertension based on aortic BP, and the predictive value of brachial BP for aortic hypertension was poor (positive-predictive value = 13.8%). Participants with aortic hypertension had a higher left ventricular mass index than those with brachial hypertension. CONCLUSION: Brachial BP substantially overestimates aortic BP in adolescents because of marked aortic-to-brachial pulse pressure amplification. The use of brachial BP measurement may result in an overdiagnosis of hypertension during screening in adolescence.

Medical device regulation in vascular ageing assessment: a VascAgeNet survey exploring knowledge and perception.

BACKGROUND: Regulation has a key role for medical devices throughout their lifecycle aiming to guarantee effectiveness and safety for users. Requirements of Regulation (EU) 2017/745 (MDR) have an impact on novel and previously approved systems. Identification of key stakeholders' needs can support effective implementation of MDR improving the translation to clinical practice of vascular ageing assessment. The aim of this work is to explore knowledge and perception of medical device regulatory framework in vascular ageing field. RESEARCH DESIGN AND METHODS: A survey was developed within VascAgeNet and distributed in the community by means of the EUSurvey platform. RESULTS: Results were derived from 94 participants (27% clinicians, 62% researchers, 11% companies) and evidenced mostly a fair knowledge of MDR (despite self-judged as poor by 51%). Safety (83%), validation (56%), risk management (50%) were considered relevant and associated with the regulatory process. Structured support and regulatory procedures connected with medical devices in daily practice at the institutional level are lacking (only 33% report availability of a regulatory department). CONCLUSIONS: Regulation was recognized relevant by the VascAgeNet community and specific support and training in medical device regulatory science was considered important. A direct link with the regulatory sector is not yet easily available.

Developing technologies to assess vascular ageing: a roadmap from VascAgeNet.

Vascular ageing is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges.

Leveraging deep learning models to understand the daily experience of anxiety in teenagers over the course of a year.

INTRODUCTION: Anxiety disorders are a prevalent and severe problem that are often developed early in life and can disrupt the daily lives of affected individuals for many years into adulthood. Given the persistent negative aspects of anxiety, accurate and early assessment is critical for long term outcomes. Currently, the most common method for anxiety assessment is through point-in-time measures like the GAD-7. Unfortunately, this survey and others like it can be subject to recall bias and do not fully capture the variability in an individual's day-to-day symptom experience. The current work aims to evaluate how point-in-time assessments like the GAD-7 relate to daily measurements of anxiety in a teenage population. METHODS: To evaluate this relationship, we leveraged data collected at four separate three week intervals from 30 teenagers (age 15-17) over the course of a year. The specific items of interest were a single item anxiety severity measure collected three times per day and end-of-month GAD-7 assessments. Within this sample, 40 % of individuals reported clinical levels of generalized anxiety disorder symptoms at some point during the study. The first component of analysis was a visual inspection assessing how daily anxiety severity fluctuated around end-of-month reporting via the GAD-7. The second component was a between-subjects comparison assessing whether individuals with similar GAD-7 scores experienced similar symptom dynamics across the month as represented by latent features derived from a deep learning model. With this approach, similarity was operationalized by hierarchical clustering of the latent features. RESULTS: The aim clearly indicated that an individual's daily experience of anxiety varied widely around what was captured by the GAD-7. Additionally, when hierarchical clustering was applied to the three latent features derived from the (LSTM) encoder (r = 0.624 for feature reconstruction), it was clear that individuals with similar GAD-7 outcomes were experiencing different symptom dynamics. Upon further inspection of the latent features, the LSTM model appeared to rely as much on anxiety variability over the course of the month as it did on anxiety severity (p < 0.05 for both mean and RMSSD) to represent an individual's experience. DISCUSSION: This work serves as further evidence for the heterogeneity within the experience of anxiety and that more than just point-in-time assessments are necessary to fully capture an individual's experience.

Does 3D-speckle tracking echocardiography improve prediction of major cardiovascular events in a multi-ethnic general population? A Southall and Brent Revisited (SABRE) cohort study.

3D-speckle tracking echocardiography(3D-STE) allows simultaneous assessment of ejection fraction(EF) and multidirectional strains, but its prognostic utility in the general population is unknown. We investigated if 3D-STE strains predicted a composite of major cardiac endpoints(MACE) beyond cardiovascular risk factors(CVDRF), and whether they were superior to 3D-EF. 529 participants in SABRE, a UK-based tri-ethnic general population cohort (69±6y; 76.6% male) with acceptable 3D-STE imaging were studied. Associations between 3D-EF or multidirectional myocardial strains and MACE(coronary heart disease(fatal/non-fatal), heart failure hospitalization, new-onset arrhythmia and cardiovascular mortality) were determined using Cox regression including adjustment for CVDRF and 2D-EF. Whether 3D-EF, global longitudinal strain(3D-GLS) and principle tangential strain(3D-PTS/3D-strain) improved cardiovascular risk stratification over CVDRF was investigated using a likelihood ratio test on a series of nested Cox proportional hazards models and Harrell's C statistics. During follow-up(median, 12y), there were 92 events. 3D-EF, 3D-GLS and 3D-PTS and 3D-RS were associated with MACE in unadjusted and models adjusted for CVDRF but not CVDRF+2D-EF. Compared to 3D-EF, both 3D-GLS and 3D-PTS slightly improved the predictive value over CVDRF for MACE, but the improvement was modest(C statistic increased from 0.698(0.647, 0.749) to 0.715(0.663, 0.766) comparing CVDRF with CVDRF +3D-GLS). 3D-STE-derived LV myocardial strains predicted MACE in a multi-ethnic general population sample of elderly individuals from the UK; however the added prognostic value of 3D-STE myocardial strains was small.

Developing a Questionnaire on Knowledge, Perceptions and Application of Vascular-Aging Measurements.

BACKGROUND: Vascular age (VA) is independent and chronological age for assessing cardiovascular disease (CVD) risk. However, tools for the implementation of VA are currently lacking. We aimed to develop a questionnaire to assess the current knowledge gaps related to VA and barriers to its implementation in routine practice. METHODS: Using a stepwise mixed-method approach, a quantitative questionnaire was constructed in four phases: (1) basic item generation and the development of a semi-qualitative questionnaire (SQQ); (2) dissemination to the VascAgeNet extended network and an analysis of the semi-qualitative questionnaire responses; (3) the development of a quantitative questionnaire (QQ); and (4) an assessment of the content and face validity and internal reliability in an additional sample. RESULTS: Based on six main topics initially identified through an expert panel, a SQQ was developed and disseminated. Finally, a 22-item QQ was developed, with questions grouped around three main themes: knowledge of VA and its risk factors; perceptions and beliefs regarding the importance and contribution of VA to risk classification; and the application of VA measurements in clinical and research practice and its potential limitations (Cronbach's alpha between 0.920 and 0.982 for all three categories). CONCLUSION: We report the development of a QQ on VA addressed to both clinicians and non-clinicians aiming to assess their knowledge, perceptions and application of VA measurements.

Sex-differences in associations of LV structure and function measured by echocardiography with long-term risk of mortality and cardiovascular morbidity.

Background: Three-dimensional echocardiography (3DE) measures of the left ventricle (LV) predict outcomes in high risk individuals, but their prognostic value in the general population is unknown. We aimed to establish whether 3DE was associated with mortality and morbidity in a multi-ethnic community-based sample, if associations differed by sex, and explored potential mechanisms explaining sex differences. Methods: 922 individuals (69.7 ± 6.2 years; 717 men) from the SABRE study underwent a health examination including echocardiography. Associations between 3DE LV measures (ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), LV remodeling index (LVRI) and LV sphericity index (LVSI), and all-cause mortality and a composite cardiovascular endpoint [comprising new onset (non)fatal coronary heart disease, heart failure hospitalization, new-onset arrhythmias and cardiovascular mortality] were determined using multivariable Cox regression over a median follow-up of 8 years (all-cause mortality) and 7 years (composite cardiovascular endpoint). Results: There were 123 deaths and 151 composite cardiovascular endpoints. Lower EF, higher LV volumes and LVSI were associated with increased all-cause mortality, and higher LV volumes were associated with the composite cardiovascular endpoint independent of potential confounders. Associations between LV volumes, LVRI, LVSI, and mortality differed by sex (p interaction <0.1). In men increased LV volumes and LVSI and decreased LVRI and EF were associated with higher mortality, but associations were null or reversed in women (hazard ratios (95% CI) men vs. women: EDV 1.25 (1.05, 1.48) vs. 0.54 (0.26, 1.10); ESV, 1.36 (1.12, 1.63) vs. 0.59 (0.33, 1.04); LVRI, 0.79 (0.64, 0.96) vs. 1.70 (1.03, 2.80); LVSI, 1.27 (1.05, 1.54) vs. 0.61 (0.32, 1.15); and EF, 0.78 (0.66, 0.93) vs. 1.27 (0.69, 2.33). Similar sex differences were observed for associations with the composite cardiovascular outcome. Adjustment for LV diastolic stiffness and arterial stiffness marginally attenuated these differences. Conclusions: 3DE measures of LV volume and remodeling are associated with all-cause mortality and cardiovascular morbidity; however, some associations differ by sex. Sex-differences in LV remodeling patterns may influence mortality and morbidity risk in the general population.

Plasma cell differentiation, antibody quality, and initial germinal center B cell population depend on glucose influx rate.

Antibody secretion into sera, selection for higher affinity BCR, and the generation of higher Ab affinities are important elements of immune response optimization, and a core function of germinal center reactions. B cell proliferation requires nutrients to support the anabolism inherent in clonal expansion. Glucose usage by GC B cells has been reported to contribute little to their energy needs, with questions raised as to whether or not glucose uptake or glycolysis increases in GC B cells compared to their naïve precursors. Indeed, metabolism can be highly flexible, such that supply shortage along one pathway may be compensated by increased flux on others. We now show that elimination of the glucose transporter GLUT1 after establishment of a pre-immune B cell repertoire, even after initiation of the GC B cell gene expression program, decreased initial GC B cell population numbers, affinity maturation, and PC outputs. Glucose oxidation was heightened in GC B cells, but this hexose flowed more into the pentose phosphate pathway (PPP), whose activity was important in controlling reactive oxygen (ROS) and ASC production. In modeling how glucose usage by B cells promotes the Ab response, the control of ROS appeared insufficient. Surprisingly, the combination of galactose, which mitigated ROS, with provision of mannose - an efficient precursor to glycosylation - supported robust production of and normal Ab secretion by ASC under glucose-free conditions. Collectively, the findings indicate that GC depend on normal glucose influx, especially in PC production, but reveal an unexpected metabolic flexibility in hexose requirements. KEY POINTS: Glucose influx is critical for GC homeostasis, affinity maturation and the generation of Ab-secreting cells.Plasma cell development uses the Pentose Phosphate Pathway, and hexose sugars maintain redox homeostasis.PCs can develop and achieve robust Ab secretion in the absence of glucose using a combination of hexose alternatives.

Is Height2.7 Appropriate for Indexation of Left Ventricular Mass in Healthy Adolescents? The Importance of Sex Differences.

BACKGROUND: Left ventricular mass (LVM) is an important predictor of cardiovascular risk. In adolescence, LVM is commonly indexed to height2.7, although some evidence suggests that this may not fully account for sex differences. METHODS: We investigated appropriate allometric scaling of LVM to height, total lean mass, and body surface area, in a UK birth cohort of 2039 healthy adolescents (17±1 years). Allometric relationships were determined by linear regression stratified by sex, following log transformation of x and y variables [log(y)=a+b×log(x)], b is the allometric exponent. RESULTS: Log (LVM) showed linear relationships with log(height) and log(lean mass). Biased estimates of slope resulted when the sexes were pooled. The exponents were lower than the conventional estimate of 2.7 for males (mean [95% CI]=1.66 [1.30-2.03]) and females (1.58 [1.27-1.90]). When LVM was indexed to lean mass, the exponent was 1.16 (1.05-1.26) for males and 1.07 (0.97-1.16) for females. When LVM was indexed to estimated body surface area, the exponent was 1.53 (1.40-1.66) for males and 1.34 (1.24-1.45) for females. CONCLUSIONS: Allometric exponents derived from pooled data, including men and women without adjustment for sex were biased, possibly due to sex differences in body composition. We suggest that when assessing LVM, clinicians should consider body size, body composition, sex, and age. Our observations may also have implications for the identification of young individuals with cardiac hypertrophy.